Distribution of factor H binding protein beyond serogroup B: variation among five serogroups of invasive Neisseria meningitidis in South Africa

Factor H binding protein (fHBP) is currently under investigation as a potential vaccine antigen for protection against meningococcal serogroup B (MenB) disease. This study describes the distribution of genotypes among all (n = 58) MenB, and a total of 80 representative non-MenB (serogroups A, C, Y and W135) isolates causing invasive disease in South Africa in 2005 using fHBP sequence analysis, PorA, FetA and multilocus sequence typing. There was less fHBP diversity among non-MenB isolates compared to MenB isolates. fHBP subfamily variant A32 was the most common fHBP variant among MenB isolates and was represented by 17% (10/58) of the isolates, while fHBP variant B16 was the most prevalent variant among non-MenB strains and was represented by 40% (32/80) of isolates. Overall, subfamily B domain N6 (modular group I) was most prevalent (57%, 79/138). Twenty PorA and 16 FetA types were identified among MenB isolates whereas non-MenB serogroups were largely associated with specific serosubtypes. The most common MenB clonal complex (ST-41/44/lineage 3) was represented by 29% (17/58) of the MenB isolates, while each of the non-MenB serogroups had a major clone represented by at least 75% of the isolates within the serorogroup. Our data highlight that non-MenB meningococcal isolates also harbor fHBP.     

Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine in toddlers and school children

Though meningococcal conjugate vaccines are effective against serogroup C, there is currently no vaccine solution for serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results. However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes. By using five wild type P1.19,15 variant strains we examined the serum bactericidal antibody (SBA) titres from sera collected from toddlers and school children pre- and post-vaccination. The numbers of subjects with SBA titres of <4, 4 and > or = 8 varied greatly between the different strains. This was also reflected when > or = 4-fold rises in SBA titres were examined. This finding in sera from toddlers and school children may have implications for PorA based vaccines.     

Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine

Though meningococcal serogroup C conjugate vaccines have been introduced into the UK infant immunisation schedule, there is currently no vaccine solution for serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results. This vaccine contains six different PorA OMPs each representing a different serosubtype. However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes. By using recombinant P1.5,10 PorA variants we have demonstrated that the killing of this particular serosubtype combination was due mainly to the induction of antibody to the VR2 (P1.10) epitope region, and that after three or four doses of vaccine there was a significant reduction in the killing of variants P1.10a (three doses, p<0.0001; four doses, p = 0.003) and P1.10f (three doses, p<0.0001; four doses, p = 0.002), as compared to responses to the P1.10 strain, when the P1.10 serosubtype was used as the immunogen. Since large numbers of serosubtype variants are known to exist, this finding may have implications for the use of PorA as a meningococcal serogroup B vaccine.     

Predicted coverage by 4CMenB vaccine against invasive meningococcal disease cases in the Netherlands

Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease in Europe. In the absence of a conjugate serogroup B vaccine, a subcapsular 4CMenB vaccine was developed. Data on 4CMenB vaccine efficacy is still limited. Recently, genomic MATS (Meningococcal Antigen Typing System) was developed as a tool to predict strain coverage, using vaccine antigens sequence data. We characterized all invasive meningococcal isolates received by the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM) in two epidemiological years 2017–2019 using whole-genome sequencing and determined serogroup, clonal complex (cc) and estimated 4CMenB vaccine coverage by gMATS. Of 396 cases of invasive meningococcal disease, corresponding to an incidence of 1.22 cases/10⁵ inhabitants, 180 (45%) were serogroup W, 155 (39%) serogroup B, 46 (12%) serogroup Y, 10 (3%) serogroup C, 2 non-groupable (0.5%) and 3 (0.7%) unknown. The incidence was the highest among 0–4 years olds (4 cases/10⁵ inhabitants), and 57/72 (79%) of these cases were serogroup B. Serogroup W predominated among persons 45 years of age or older with 110/187 (59%) cases. Serogroup B isolates comprised 11 different clonal complexes, with 103/122 (84%) isolates belonging to 4 clonal complexes: cc32, cc41/44, cc269 and cc213. In contrast, serogroup W isolates were genetically similar with 95% belonging to cc11. Of 122 serogroup B isolates, 89 (73%; 95% CI: 64–80%) were estimated to be covered by 4CMenB and the degree of coverage varied largely by clonal complex and age. Among the 0–4 year olds, 25 of 43 (58%; 95% CI: 43–72%) MenB isolates were estimated to be covered. Since the coverage of the 4CMenB vaccine is dependent on circulating clonal complexes, our findings emphasize the need for surveillance of circulating meningococcal strains. In addition, estimation of age specific coverage is relevant to determine the right target age group for vaccination.     

Immunogenicity of a combination vaccine containing pneumococcal conjugates and meningococcal PorA OMVs

The pre-clinical immunogenicity of a combination vaccine containing 13-valent pneumococcal conjugate (13vPnC) vaccine (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F conjugated to CRM197) and nine-valent meningococcal B PorA vaccine (NonaMen; serosubtypes P1.7,16; P1.5-1,2-2; P1.19,15-1; P1.5-2,10; P1.12-1,13; P1.7-2,4; P1.22,14; P1.7-1,1 and P1.18-1,3,6), and any potential immunological interference between pneumococcal and MenB components of the vaccine were evaluated. NIH mice were immunized twice subcutaneously with the vaccines combined in one syringe, or given individually. Combining 13vPnC vaccine with NonaMen vaccine in one syringe had no negative effect on the induced antibody response against any MenB serosubtypes compared to separate injection of the vaccines, and the anti-pneumococcal antibody responses were enhanced. Furthermore, co-administration of the combination vaccine with a combined diphtheria/tetanus/acellular pertussis/inactivated poliomyelitis vaccine/Haemophilus influenzae type b-TT conjugate (DTaP/IPV-Hib) vaccine to New Zealand white rabbits at a different injection site did not affect the anti-pneumococcal polysaccharide and anti-PorA antibody titres. We conclude that no immunological interference was observed by combined administration of pneumococcal conjugate and meningococcal B vaccines in one syringe.     

Immunogenicity and bactericidal activity in mice of an outer membrane protein vesicle vaccine against Neisseria meningitidis serogroup A disease

Serogroup A Neisseria meningitidis organisms of the subgroup III have caused epidemics of meningitis in sub-Saharan Africa since their introduction into the continent in 1987. The population structure of these bacteria is basically clonal, and these meningococci are strikingly similar in their major outer membrane antigens PorA and PorB. Protein-based vaccines might be an alternative to prevent epidemics caused by these meningococci; thus, we developed an outer membrane vesicle (OMV) vaccine from a serogroup A meningococcal strain of subgroup III. The serogroup A OMV vaccine was highly immunogenic in mice and elicited significant bactericidal activity towards several other serogroup A meningococci of subgroup III. The IgG antibodies generated were in immunoblot shown to be mainly directed towards the PorA outer membrane protein. The results presented demonstrate the potential of an OMV vaccine as an optional strategy to protect against meningococcal disease caused by serogroup A in Africa.     

Phenotypic assessment of Neisseria meningitidis isolates obtained from patients with invasive meningococcal disease in Greece, 1993-2003: implications for serogroup B vaccines based on PorA serosubtype antigens

Serogroup B is the major isolate from patients with invasive meningococcal disease (IMD) in Greece. This study used the whole cell enzyme-linked immuosorbent assay (ELISA) with monoclonal antibodies to screen Neisseria meningitidis isolates obtained from patients with IMD between 1993 and 2003 to determine if serosubtypes included in the hexavalent Por A OMP vaccines being tested in northern Europe were prevalent in Greece. During this period there were significant changes in the proportions of serogroups B and C isolated from patients. Serogroup C was predominant in 1996-1997 but fell sharply with corresponding increases in serogroup B. Of the 591 isolates sent to the National Meningitis Reference Laboratory in Athens during this period, 325 (55%) were serogroup B. Among those tested for serosubtype, porA proteins used for the vaccine being tested in Britain were detected on 85/284 (30%) strains and for the vaccine being tested in the Netherlands 175/284 (62%). P1.14 (58/284, 20%) the predominant serosubtype among the Greek isolates, is not present in either vaccine formulation; 23/284 (8%) strains did not react with any of the monoclonal antibodies. Our results indicate that introduction of the vaccines currently being evaluated in northern Europe would not be warranted in the Greek population.     

Heterologous prime-boost strategy to overcome weak immunogenicity of two serosubtypes in hexavalent Neisseria meningitidis outer membrane vesicle vaccine

In the hexavalent meningococcal B OMV vaccine (HexaMen), two of the six Porin A proteins present are weakly immunogenic in mice and humans. We investigated the possibility that the lower immunogenicity of these serosubtypes (P1.7-2,4 and P1.19,15-1) could be overcome by using HexaMen and monovalent OMVs in heterologous immunisation protocols. Whereas HexaMen priming on day 0 followed by a monovalent P1.7-2,4 OMV boosting on day 28 (specific boost) did not result in higher titres against P1.7-2,4 (on day 42), the reverse order of immunisations (specific priming) resulted in significantly higher ELISA and SBA titres, but with lower avidity. For the strongly immunogenic PorA P1.5-1,2-2, all strategies gave high antibody responses, while avidity was highest after two monovalent P1.5-1,2-2 OMV immunisations. Based on the improved antibody titres obtained by specific priming with the weakly immunogenic PorA, we extended our study with combined P1.7-2,4 and P1.19,15-1 priming followed by two HexaMen booster immunisations. This resulted in higher ELISA and SBA titres against these weakly immunogenic PorAs, while the response against the other four PorAs was unaffected. Also, we observed an increase in antibody avidity using this schedule, indicating that affinity maturation has occurred. In conclusion, we found that specific priming, rather than specific boosting with monovalent OMVs, gave a significant rise in the serosubtype-specific immune response against a weakly immunogenic PorA, with high avidity antibodies in an extended immunisation schedule.     

IgG antibody subclass responses determined by immunoblot in infants' sera following vaccination with a meningococcal recombinant hexavalent PorA OMV vaccine

The introduction of meningococcal serogroup C conjugate vaccines into the UK immunisation schedule has led to the decline of serogroup C disease in those vaccinated but there is no imminent vaccine solution for serogroup B disease. The PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate and an outer membrane vesicle (OMV) vaccine containing six different PorA OMPs (each representing a different serosubtype) has been evaluated in phase II trials with encouraging results. Little is known about the IgG subclass response to the various antigens contained within this vaccine. These responses are important due to the different half-lives and complement fixing abilities of these antibodies. In this study, immunoblotting was undertaken with infants' sera following either three or four doses of vaccine, and OMVs from six isogenic meningococcal strains differing only in their PorA serosubtype. Following either three or four doses of the vaccine, IgG(3) and IgG(1) subclass antibodies were induced to all six of the isogenic strains, although sera collected after four doses of vaccine showed stronger antibody levels. IgG(3) was found in more sera than IgG(1). For both sets of sera, the two isogenic strains expressing P1.5,2 and P1.5(c),10 induced stronger IgG subclass antibody responses than the other four meningococcal strains. The recombinant hexavalent PorA OMV vaccine stimulates both IgG(1) and IgG(3) subclass antibodies, the subclasses that are most effective in activating the complement system.     

Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2-3 and 7-8 years of age

To study the reactogenicity and immunogenicity of a hexavalent meningococcal outer-membrane-vesicle vaccine (OMV), two different dosages of this vaccine (7.5 and 15 microg of individual PorA proteins) consisting of vesicles expressing class 1 outer-membrane proteins (OMPs) of subtypes P1.7,16; P1.5,2; P1.19,15 and P1.5(c), 10; P1.12,13; P1.7(h),4 were administered to a group of 7-8 year (n=165) and a group of 2-3 year old children (n=172). Control groups of children with similar ages were vaccinated against hepatitis B. All participants received three injections. Pre- and postimmunisation sera were tested for bactericidal antibodies against six isogenic meningococcal vaccine strains expressing different PorA proteins. Antibody titres against OMP of the two different vesicles (PL16215 and PL10124) were measured by ELISA. The meningococcal hexavalent OMV vaccine was well tolerated. No statistically significant differences were seen between the high and low dose of hexavalent meningococcal OMV vaccine. The percentage of children showing a fourfold increase of bactericidal antibody titres against the specific serosubtype varied in toddlers from 28 to 98% and in older children from 16 to 100%. Both ELISA antibody titres and bactericidal activity showed the highest level in the youngest age-group.     

Vaccines against Neisseria meningitidis serogroup B strains – What does genomics reveal on the Portuguese strain’s coverage

In Portugal, Neisseria meningitidis serogroup B (MenB) is the most common serogroup causing invasive meningococcal disease. To protect against MenB disease two protein based MenB vaccines are available in Portugal, the 4CMenB that was licenced in 2014 and included in the routine immunization program in October 2020, and the bivalent rLP2086 vaccine licensed in 2017. The aim of this study was to predict the coverage of the 4CMenB and rLP2086 vaccines against Portuguese isolates of Neisseria meningitidis sampled between 2012 and 2019 and to evaluate the diversity of vaccine antigens based on genomic analysis.Whole-genome sequence data from 324 Portuguese Neisseria meningitidis isolates were analysed. To predict strain coverage by 4CMenB and rLP2086, vaccine antigen reactivity was assessed using the MenDeVar index available on the PubMLST Neisseria website.This study included 235 (75.6%) MenB isolates of all invasive MenB strains reported between 2012 and 2019. Moreover, 89 non MenB isolates sampled in the same period, enrolling 68 from invasive disease and 21 from healthy carriers, were also studied.The predicted strain coverage of MenB isolates was 73.5% (95% CI: 64.8%–81.2%) for 4CMenB and 100% for rLP2086. Predicted strain coverage by 4CMenB in the age group from 0 to 4 years old, was 73.9%. Most of MenB isolates were covered by a single antigen (85.4%), namely fHbp (30.3%), P1.4 (29.2%), and NHBA (24.7%).In Portugal, the most prevalent peptides in MenB isolates were: P1.4 (16.2%), NHBA peptide 2 (14.0%), and fHbp peptide 14 (7.2%), from 4CMenB and fHbp peptide 19 (10.6%) from rLP2086. No significant temporal trends were observed concerning the distribution and diversity of vaccine antigen variants.4CMenB and rLP2086 vaccines showed potential coverage for isolates regardless serogroup.The use of both vaccines should be considered to control possible outbreaks caused by serogroups with no vaccine available.     

High predicted strain coverage by the multicomponent meningococcal serogroup B vaccine (4CMenB) in Poland

Neisseria meningitidis of serogroup B (MenB) is currently responsible for more than 70% of cases of invasive meningococcal disease (IMD) in Poland and Europe as a whole. The aim of this study was to estimate strain coverage of a multicomponent meningococcal serogroup B vaccine (4CMenB) in Poland; the meningococcal antigen typing system (MATS) was used to test a panel of 196 invasive MenB strains isolated in Poland in 2010 and 2011. The strains were also characterized by MLST and sequencing of porA, factor H-binding protein (fHbp), Neisserial heparin-binding antigen (nhba) and Neisserial adhesin A (nadA) genes. MATS and molecular data were analyzed independently and in combination. The MATS results predicted that 83.7% (95% CI: 78.6–91.0%) of isolates would be covered by the 4CMenB vaccine; 59.2% by one vaccine antigen, 19.9% by two and 4.6% by three antigens. Coverage by each antigen was as follows: fHbp 73.0% (95% CI: 68.9–77.5%), NHBA 28.6% (95% CI: 13.3–47.4%), NadA 1.0% (95% CI: 1.0–2.0%) and PorA 10.2%. Molecular analysis revealed that the most frequent clonal complexes (ccs) were cc32 (33.2%), cc18 (17.9%) and cc41/44 (15.8%) with estimated coverage of 98.5%, 88.6% and 93.5%, respectively.Consistent with findings for other European countries, our study predicts high coverage by the 4CMenB vaccine in Poland.     

Estimated susceptibility of Canadian meningococcal B isolates to a meningococcal serogroup B vaccine (MenB-FHbp)

BackgroundInvasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) remains a health risk in Canada and globally. Two MenB vaccines are now approved for use. An understanding of the genotype of Canadian strains and the potential strain coverage conferred by the MenB-FHbp vaccine is needed to inform immunization policies.MethodsSerogroup B Neisseria meningitidis strains responsible for meningococcal disease in Canada from 2006 to 2012 were collected as part of the Canadian Immunization Monitoring Program Active surveillance network. Genotypic analysis was done on MenB isolates from 2006 to 2012 with determination of fHbp surface expression for a subset of isolates: those occurring from 2010 to 2012.ResultsTwo clonal complexes (cc269 and cc41/44) were observed in 68.8% of the 276 isolates. A total of 50 different fHbp peptides were identified among isolates from 2006 to 2012. Surface expression of fHbp was detected on 95% of MenB isolates from 2010 to 2012 and 91% of isolates expressed fHbp at levels that are predicted to be susceptible to the bactericidal immune response elicited by the MenB-FHbp vaccine. Some regional differences were observed, particularly in isolates from British Columbia and Quebec.ConclusionThe majority of MenB isolates responsible for meningococcal disease in Canada expressed fHbp at levels predicted to be sufficient for complement mediated bactericidal activity in the presence of MenB-FHbp induced serum antibodies.     

Annual report of the Australian Meningococcal Surveillance Programme, 1998. The Australian Meningococcal Surveillance Programme

The National Neisseria Network has undertaken meningococcal isolate surveillance by means of a collaborative laboratory-based initiative since 1994. The phenotype (serogroup, serotype and serosubtype) and antibiotic susceptibility of 323 isolates of Neisseria meningitidis from invasive cases of meningococcal disease were determined in 1998. Ninety per cent of the invasive isolates were either serogroup B or C. Serogroup B strains predominated in all States and Territories and were isolated from sporadic cases of invasive disease. Serogroup B phenotypes were diverse. Serogroup C isolates were most prominent in New South Wales, especially in adolescents and young adults. C:2a:P1.5 was the most frequently encountered phenotype and C:2b:P1.5,2 strains were also distributed widely. About three-quarters of all isolates showed decreased susceptibility to the penicillin group of antibiotics (MIC 0.06 to 0.5 mg/L). Four isolates showed reduced susceptibility to rifampicin, one to ciprofloxacin and one to chloramphenicol.     

Genetic variability of Polish serogroup B meningococci (2010–2016) including the 4CMenB vaccine component genes

Neisseria meningitidis serogroup B (MenB) has recently become the major cause of invasive meningococcal disease in Poland. Therefore, the purpose of this study was to characterize MenB isolates, responsible for invasive meningococcal disease in 2010–2016, by MLST and sequencing of genes encoding proteins used as 4CMenB vaccine antigens. Two methods of coverage estimation were performed: extrapolation of MATS results of Polish meningococci 2010–2011 (exMATS) and gMATS, which combines genotyping and MATS results.Among 662 isolates 20 clonal complexes (CC) were detected, of which the most frequent were CC32, CC41/44 and CC18, accounting for 31.9%, 16.5% and 12.7%, respectively. A total of 111 combinations of PorA variable regions (VR1/VR2) were found, with P1.7,16 (15.0%) and P1.22,14 (13.6%) being prevalent. Vaccine variant VR2:4 was detected in 7.3% of isolates, mainly representing CC41/44 and non-assigned CC. Eighty five fHbp alleles encoding 74 peptide subvariants were revealed. Subvariant 1.1, a component of 4CMenB, was prevalent (24.2%) and found generally in CC32. Typing of the nhba gene revealed 102 alleles encoding 87 peptides. The most frequent was peptide 3 (22.4%), whereas vaccine peptide 2 was detected in 9.8%, mostly among CC41/44. The nadA gene was detected in 34.0% of isolates and the most prevalent was peptide 1 (variant NadA-1; 71.6%), found almost exclusively in CC32 meningococci. Vaccine peptide 8 (variant NadA-2/3) was identified once. Consequently, 292 completed BAST profiles were revealed. Regarding vaccine coverage, 39.7% of isolates had at least one 4CMenB vaccine variant, but according to exMATS and gMATS the coverage was 83.3% and 86.6%, respectively.In conclusion, Polish MenB (2010–2016) was highly diverse according to MLST and gene alleles encoding 4CMenB vaccine antigens. Some correlations between clonal complexes and variants of examined proteins/BAST profiles were revealed and a high coverage of 4CMenB vaccine was estimated.     

Multicomponent meningococcal serogroup B vaccination elicits cross-reactive immunity in infants against genetically diverse serogroup C,W and Y invasive disease isolates

BackgroundThe multicomponent meningococcal serogroup B vaccine (4CMenB) is currently indicated for active immunization against invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB). However, genes encoding the 4CMenB antigens are also variably present and expressed in strains belonging to other meningococcal serogroups. In this study, we evaluated the ability of antibodies raised by 4CMenB immunisation to induce complement-mediated bactericidal killing of non-MenB strains.MethodsA total of 227 invasive non-MenB disease isolates were collected between 1 July 2007 and 30 June 2008 from England and Wales, France, and Germany; 41 isolates were collected during 2012 from Brazil. The isolates were subjected to genotypic analyses. A subset of 147 isolates (MenC, MenW and MenY) representative of the meningococcal genetic diversity of the total sample were tested in the human complement serum bactericidal antibody assay (hSBA) using sera from infants immunised with 4CMenB.ResultsSerogroup and clonal complex repertoires of non-MenB isolates were different for each country. For the European panel, MenC, MenW and MenY isolates belonged mainly to ST-11, ST-22 and ST-23 complexes, respectively. For the Brazilian panel, most MenC and MenW isolates belonged to the ST-103 and ST-11 complexes, respectively, and most MenY isolates were not assigned to clonal complexes. Of the 147 non-MenB isolates, 109 were killed in hSBA, resulting in an overall coverage of 74%.ConclusionThis is the first study in which 147 non-MenB serogroup isolates have been analysed in hSBA to evaluate the potential of a MenB vaccine to cover strains belonging to other serogroups. These data demonstrate that antibodies raised by 4CMenB are able to induce bactericidal killing of 109 non-MenB isolates, representative of non-MenB genetic and geographic diversity. These findings support previous evidence that 4CMenB immunisation can provide cross-protection against non-MenB strains in infants, which represents an added benefit of 4CMenB vaccination.     

Annual report of the Australian Meningococcal Surveillance Programme, 1999

The National Neisseria Network has undertaken meningococcal isolate surveillance by means of a collaborative laboratory based initiative since 1994. The phenotype (serogroup, serotype and serosubtype) and antibiotic susceptibility of 368 isolates of Neisseria meningitidis from invasive cases of meningococcal disease were determined in 1999. Ninety percent of the invasive isolates were either serogroup B or C. Serogroup B strains predominated in all States and Territories and were isolated from sporadic cases of invasive disease. Serogroup B phenotypes were generally diverse, but in New South Wales phenotype B:4:P1.4(7) became more prominent. The number of serogroup C isolates increased significantly in Victoria and remained prominent in New South Wales, especially in adolescents and adults. Phenotype C:2a:P1.2, infrequently isolated prior to 1999, was the most frequently encountered serogroup C phenotype. A number of infections with a phenotype new to Australia, C:2a:P1.4(7), were noted in Victoria and to a lesser extent in New South Wales. Phenotype C:2a:P1.5 was less frequently encountered than in previous years. About three-quarters of all isolates showed decreased susceptibility to the penicillin group of antibiotics (MIC 0.06 to 0.5 mg/L). Three isolates showed reduced susceptibility to rifampicin. Data relating to 92 laboratory-confirmed but culture-negative cases were included in this report. Some differences in the patterns of disease were revealed when culture-based and non-culture-based data were compared.     

Characterization of invasive Neisseria meningitidis isolates recovered from children in Turkey during a period of increased serogroup B disease, 2013–2017

Diverse Neisseria meningitidis strains belonging to various serogroups and clonal complexes cause epidemic and endemic life-threatening disease worldwide. This study aimed to investigate the genetic diversity of recent invasive meningococci in Turkey with respect to multilocus sequence type (MLST) and also meningococcal serogroup B (MenB) vaccine antigens to enable assessment of potential MenB strain coverage using the genetic Meningococcal Antigen Typing System (gMATS). Fifty-four isolates, representing 37.5% of all pediatric (ages 0–18 years) invasive meningococcal disease cases in Turkey from January 2013 to December 2017, underwent genome sequence analysis. Thirty-six (66.7%) isolates were MenB, 10 (18.5%) were serogroup W (MenW), 4 (7.4%) were serogroup A (MenA), 3 (5.6%) were serogroup Y (MenY) and 1 (1.8%) was serogroup X (MenX). The MenB isolates were diverse with cc35 (19.4%), cc41/44 (19.4%) and cc32 (13.8%) as the most prevalent clonal complexes. The MenW isolates (n = 10) comprised cc11 (n = 5), ST-2754 (cc-unassigned; n = 4) and cc22 (n = 1). gMATS was indicative of high 4CMenB coverage (72.2–79.1%) of Turkish invasive MenB strains from pediatric patients. Strain coverage of several clonal complexes differed from that seen elsewhere in Europe highlighting the importance of performing local assessments and also the use of phenotypic methods, i.e. MATS, where possible. All of the isolates possessed in-frame fhbp alleles and so were potentially covered by MenB-fHbp. Continued surveillance is essential to guide recommendations for current and future vaccines as well as understanding changes in epidemiology.     

Deletion of major porins from meningococcal outer membrane vesicle vaccines enhances reactivity against heterologous serogroup B Neisseria meningitidis strains

Detergent-extracted detoxified outer membrane vesicle (dOMV) vaccines are effective at preventing invasive serogroup B meningococcal (MenB) disease caused by the homologous Neisseria meningitidis strain from which they are produced, but offer limited protection from heterologous strains. Differences in vaccine efficacy are partially due to strain-specific variations in the antigenic sequence types and expression levels of outer membrane proteins (OMPs), including the immunodominant OMP PorA. In this study, dOMV vaccines deficient in major OMPs, including PorA, PorB, and RmpM were isolated and used to immunize rabbits and mice. Serum samples were obtained from each animal and tested for antibody responses against five MenB strains. Immunization with wild type dOMVs elicited antibodies to major antigens including PorA, PorB, RmpM, and lipooligosaccharide (LOS), and demonstrated limited bactericidal activity against heterologous strains. In contrast, OMP-deficient dOMV vaccines elicited broadly cross-reactive bactericidal antibodies, with PorA/PorB-dual deficient dOMVs inducing antibodies exhibiting the greatest cross-reactivity. Enhanced killing of heterologous strains correlated with binding to unique protein bands in immunoblots, suggestive of improved immunogenicity of antigens under-represented in the wild type vaccine.     

Estimated strain coverage of serogroup B meningococcal vaccines: A retrospective study for disease and carrier strains in Greece (2010–2017)

Invasive meningococcal disease (IMD) is associated with high case fatality rates and long-term sequelae among survivors. Meningococci belonging to six serogroups (A, B, C, W, X, and Y) cause nearly all IMD worldwide, with serogroup B meningococci (MenB) the predominant cause in many European countries, including Greece (~80% of all IMD). In the absence of protein-conjugate polysaccharide MenB vaccines, two protein-based vaccines are available to prevent MenB IMD in Greece: 4CMenB (Bexsero™, GlaxoSmithKline), available since 2014; and MenB-FHbp, (Trumenba™, Pfizer), since 2018. This study investigated the potential coverage of MenB vaccines in Greece using 107 MenB specimens, collected from 2010 to 2017 (66 IMD isolates and 41 clinical samples identified solely by non-culture PCR), alongside 6 MenB isolates from a carriage study conducted during 2017–2018. All isolates were characterized by multilocus sequence typing (MLST), PorA, and FetA antigen typing. Whole Genome Sequencing (WGS) was performed on 66 isolates to define the sequences of vaccine components factor H-binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisseria adhesin A (NadA). The expression of fHbp was investigated with flow cytometric meningococcal antigen surface expression (MEASURE) assay. The fHbp gene was present in-frame in all isolates tested by WGS and in 41 MenB clinical samples. All three variant families of fHbp peptides were present, with subfamily B peptides (variant 1) occurring in 69.2% and subfamily A in 30.8% of the samples respectively. Sixty three of 66 (95.5%) MenB isolates expressed sufficient fHbp to be susceptible to bactericidal killing by MenB-fHbp induced antibodies, highlighting its potential to protect against most IMD in Greece.